Fulminant hepatic failure (FHF) is a syndrome defined as necrosis of a large number of liver cells or severe impairment of liver function and hepatic encephalopathy within 8 weeks after the initial symptom or within 10 days of the on-set of jaundice in the absence of previous liver disease. It is characterized by rapid on-set, severe condition, absence of effective treatment and high mortality.
The acute inflammation and necrosis of liver cells may lead to two different diseases: acute hepatitis and fulminant hepatic failure (also called acute hepatic failure). Acute hepatitis caused by hepatitis virus is referred to as acute viral hepatitis, and the acute hepatitis caused by alcohol is called as acute alcoholic hepatitis. Although necrosis of liver cells is widely seen in all kinds of hepatitis described above, the necrosis is not so severe to lead to hepatic dysfunction. FHF is distinguished from various acute hepatitis in that awfully rapid necrosis of liver cells happens in FHF, resulting in hepatic failure due to dysfunction of the remaining normal hepatocytes, and eventually leading to extremely high mortality.
The leading cause of FHF in China is hepatitis virus infection, while other causes including medical or poison toxicosis, ischemia and anoxia, metabolic disorder, and autoimmune hepatitis, etc. Currently no medicaments are available to specifically block the acute necrosis of liver cells, and thus hepatic failure due to large quantities of hepatic cell necrosis cannot be prevented. As a result, it keeps ongoing difficult to reduce the mortality of FHF, and there is an urgent clinical need for a medicament capable of specifically and rapidly preventing acute hepatic cell necrosis, thereby treating hepatic failure.
Recent studies have revealed that binding of TNFα and its receptor is the first pathway to trigger hepatic cell necrosis, which plays an important role in the mechanism of hepatocyte impairment. Blocking said binding will block the starting point of hepatic cell necrosis, whereby enabling the pharmaceutical treatment of FHF.
At present, there are two classes of TNFα inhibitor that directly interrupt the binding of TNFα and its receptor: monoclonal antibody against TNFα, and soluble TNFα receptor analogue. These TNFα inhibitors, which bind TNFα in vivo, will theoretically prevent the binding of TNFα in blood or intercellular fluid to its receptor on the membrane of hepatocytes, thereby preventing the activation of the cell necrosis pathway.
Recent studies found that monoclonal antibody of TNFα is not a suitable candidate medicament due to its characteristic of activating TNFα on cell membrane which leads to apoptosis of the target cells, in addition to its ability to block the binding of TNFα to TNFα receptor type I.
The conventional soluble TNFα receptors can to some extent decrease the mortality in the most animal models of mild hepatic cell necrosis and acute hepatitis; however, it cannot effectively decrease the mortality of acute or sub-acute hepatic failure caused by massive hepatocyte necrosis. Furthermore, the reason of the poor therapeutic effect is still not known so far by those of the skill in the art. Consequently, it is still difficult now for the soluble TNFα receptors to find their use practically in clinical applications to treat massive hepatocytes necrosis or hepatic failure.
In summary, there is an earnest demand in the art to find the reason for the poor therapeutic effect of TNFα receptors for treating hepatic cell necrosis, so as to modify the TNFα receptors to confer it the ability to effectively and rapidly prevent the occurrence of extensive acute necrosis of hepatocytes, and thereby making it a superior medicament for clinically treating and preventing acute and sub-acute hepatic failure.